As reported in the Journal of Clinical Oncology by Akihito Kawazoe, MD, and colleagues, the final analysis of  the phase III LEAP-017 trial showed no significant overall survival benefit with lenvatinib plus pembrolizumab vs the standard of care in previously treated patients with mismatch repair–proficient (pMMR) or not microsatellite instability–high (MSI-H) metastatic colorectal cancer.

Akihito Kawazoe, MD

Study Details

The international open-label trial included 480 patients with pMMR or not–MSI-H metastatic colorectal cancer whose disease had progressed on or after, or who could not tolerate, standard treatment. They were randomly assigned between April and December 2021 to receive either lenvatinib at 20 mg orally once daily plus pembrolizumab at 400 mg once every 6 weeks (n = 241) or standard-of-care therapy (n = 239) consisting of investigator’s choice of regorafenib or trifluridine/tipiracil. Treatment continued until disease progression or unacceptable toxicity.

Overall, 32% of the enrolled patients were from Asia, 36% were from Western Europe/North America, and 32% were from the “rest of [the] world.” The primary endpoint of LEAP-017 was overall survival, with a prespecified significance threshold of P = .0214.

Overall Survival

At the final analysis, median follow-up was 18.6 months. Median overall survival was 9.8 months (95% confidence interval [CI] = 8.4–11.6 months) in patients in the lenvatinib/pembrolizumab group vs 9.3 months (95% CI = 8.2–10.9 months) in those in the standard-of-care group (hazard ratio [HR] = 0.83, 95% CI = 0.68–1.02, P = .0379)—failing to meet the prespecified significance threshold. Rates at 12 and 18 months were 42.7% vs 40.3% and 28.4% vs 19.8%, respectively.

Median progression-free survival was 3.8 months (95% CI = 3.7–5.1 months) in the lenvatinib/pembrolizumab group vs 3.3 months (95% CI = 2.0–3.7 months) in the standard-of-care group (HR = 0.69, 95% CI = 0.56–0.85); rates at 12 and 18 months were 12.8% vs 4.4% and 7.9% vs 1.5%, respectively.

Subsequent anticancer therapy was received by 46% of patients in the lenvatinib/pembrolizumab group vs 59% of those in the standard-of-care group, including chemotherapy in 41% vs 49% and targeted therapy in 10% vs 15%.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 58% of the lenvatinib/pembrolizumab group vs 42% of the standard-of-care group. The most common events in the lenvatinib/pembrolizumab group were hypertension (24%), proteinuria (11%), and diarrhea (7%); in the standard-of-care group, the most common events were neutropenia (10%) and hypertension (6%). Treatment-related adverse events led to discontinuation of any study drug in 13% vs 2% of patients. Treatment-related death occurred in two patients in the lenvatinib/pembrolizumab group (from cerebral hemorrhage and pneumonitis).

The investigators concluded: “In patients with pMMR or not–MSI-H metastatic colorectal cancer that had progressed on previous therapy, there was no statistically significant improvement in overall survival after lenvatinib plus pembrolizumab treatment vs standard of care. No new safety signals were observed.”

Dr. Kawazoe, of the National Cancer Center Hospital East, Kashiwa, Japan, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.